Our earlier mechanistic analyses of estrogen action in brain led to the discovery that estrogen is a master regulator of the bioenergetic system in brain that promotes glucose transport, glucose metabolism, mitochondrial respiration and ATP generation. Collectively, the data provided compelling evidence for estrogen as a systems biology metabolic regulator in brain and illuminated compensatory mechanisms consistent with an aging female brain that is starving. For estrogen to function as master regulator of the bioenergetic system in the female brain, estrogen must be integrating nuclear and mitochondrial genomic responses. Further from a systems level perspective, it would be necessary for estrogen to also regulate cytoplasmic signaling mechanisms for real time feedback on the functional outcomes of nuclear and mitochondrial gene transcription. The fundamental issues to be investigated are the mechanisms whereby estrogen integrates bioenergetic responses across two genomic compartments while simultaneously monitoring energetic demand and performance in real time. The proposed program of research is designed to test two hypotheses. First, estrogenic control of the bioenergetic system in the female brain requires: 1) both nuclear and mitochondrial genomes; 2) integration of gene expression across both genomic compartments and 3) activation of rapid signaling cascades to provide real time feedback on bioenergetic performance. Second, we hypothesize that loss of estrogen in the aging female brain leads to a systematic dis-integration of estrogenic control of nuclear and mitochondrial genomes followed by decline in bioenergetic sensing mechanisms. Estrogenic control of the bioenergetic system of the brain and the dismantling thereof has basic, translational and clinical significance. From a discovery perspective the proposed program of research is unique in exploring the mechanisms underlying estrogenic integration of nuclear and mitochondrial gene expression and the real time feedback mechanisms that control the bioenergetic system of the brain. Further, the process by which this control system is dismantled in the aging female brain is uncharted territory of high significance for understanding bioenergetic aging in brain. Translationally, determining the mechanisms underlying the systematic dismantling of estrogenic integration of bioenergetic compartments in brain has the potential to detect therapeutic targets to sustain bioenergetic function in the aging female brain. Clinically, the aging transition of menopause, unique to the female, is a process that dismantles both reproductive ability and potentially bioenergetic capacity in brain. This is particularly relevant to age-related neurological conditions associated with deficits in glucose hypometabolism such as Alzheimer's, depression and multiple sclerosis which have greater prevalence in postmenopausal women. Research proposed herein aligns with NIA Strategic Research Goals A and C and the ?need to better distinguish patterns of brain aging? https://www.nia.nih.gov/about/living-long-well-21st- century-strategic-directions-research-aging and to objectives of Office of Research on Women's Health.